The optimized core peptide derived from CABIN1 efficiently inhibits calcineurin-mediated T-cell activation

Abstract

The C-terminal fragment of CABIN1 interacts with calcineurin and represses the transcriptional activity of the nuclear factor of activated T cells (NFAT). However, the specific sequences and mechanisms through which it binds to calcineurin are unclear. This study determined that decameric peptide (CABIN1 residues 2146-2155) is minimally required for binding to calcineurin. This peptide contains a unique "PPTP" C-terminal sequence and a "PxIxIT" N-terminal motif. Furthermore, p38MAPK phosphorylated the threonine residue of the "PPTP" sequence under physiological conditions, dramatically enhancing the peptide's binding affinity to calcineurin. Therefore, the CABIN1 peptide inhibited the calcineurin-NFAT pathway and the activation of T cells more efficiently than the VIVIT peptide without affecting calcineurin's phosphatase activity. The CABIN1 peptide could thus be a more potent calcineurin inhibitor and provide therapeutic opportunities for various diseases caused by the calcineurin-NFAT pathway. Drug development: Potential pathway inhibitor for cancer and autoimmune diseases A peptide with therapeutic potential binds strongly to the cellular enzyme calcineurin and may prove valuable in anti-cancer and autoimmune disease treatments. Many cancers and autoimmune diseases are linked with overactivation of a key calcineurin-related pathway which is heavily involved in T cell activation. This pathway has long been a therapeutic target, but existing drugs show problems with stability and delivery, and can cause serious side effects. One known inhibitor of calcineurin is the protein CABIN1, but precisely how well it binds and how useful it may be is unclear. Now, Hong-Duk Youn at Seoul National University College of Medicine, South Korea, and co-workers have identified how one specific peptide from CABIN1 binds strongly to calcineurin. The CABIN1 peptide was stable and displayed greater efficiency at inhibiting calcineurin than another recently identified peptide candidate.